Hyperventilation with dry air damages the bronchial mucosa, increases bronchovascular permeability, degranulates mast cells, and initiates inflammation in canine peripheral airways. All of these dry air-induced phenomena are believed to contribute to the development of airways hyperreactivity in humans, and may account for the increased incidence of asthma reported in elite winter athletes. The proposed research focuses on mechanisms that may contribute to the development and persistence of chronic asthma-like symptoms in a canine model of exercise-induced asthma. The general hypothesis is that repetitive hyperventilation with dry air stimulates a nonspecific immune response that results in airways hyperreactivity. Airway mucosal cells secrete a variety of proinflammatory eicosanoids and cytokines that may play an important role in the development of nonspecific airways hyperreactivity and non-allergic asthma. The specific hypothesis is that repetitive dry air challenge (DAC) causes airway injury and stimulates a Th-2 type response that results in a persistent asthma-like state. The specific aims are to: 1) identify the stimulus responsible for repetitive hyperventilation-induced airways hyperreactivity; 2) use immunohistochemistry and image analysis to determine if repetitive hyperventilation with dry air stimulates CD4+ T lymphocyte migration; 3) identify mediators that potentially link repetitive hyperventilation-induced mucosal injury with eosinophilic inflammation in vivo using ELISA and RT-PCR; and 4) use drugs and monoclonal antibodies to investigate the role of a) eicosanoids, b) M2 receptor function, c) granulocyte infiltration, d) CD4+ lymphocyte infiltration, and e) Type-1/ Type-2 cytokine activity in the development of a repetitive DAC-induced asthma-like state. Finally, the use of a canine model will allow examination of the etiology of non-allergic small airways disease in normal dogs, and may provide valuable insights into the mechanisms involved in the development of hyperventilation-induced airway hyperreactivity and the pathogenesis of non-allergic asthma in humans.